67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
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DOI：
10.1172/jci64768
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Tachibana, Hirofumi
中科院分区：
文献类型：
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作者：
Kumazoe, Motofumi;Sugihara, Kaori;Tachibana, Hirofumi
67-kDa层粘连蛋白受体（67LR）是一种层粘连蛋白结合蛋白，在各种类型的癌症中过表达，包括胆管癌、结直肠癌、宫颈癌和乳腺癌。67LR在肿瘤细胞的生长和转移以及对化疗的抵抗中起着至关重要的作用。在这里，我们发现67LR作为一种癌症特异性死亡受体发挥作用。在这种细胞死亡受体途径中，cGMP通过激活PKC δ /酸性鞘磷脂酶（PKC δ /ASM）途径启动癌症特异性细胞死亡。此外，cGMP的上调是67LR的天然配体绿茶多酚(-)-表没食子儿茶素-3- o -没食子酸酯（EGCG）诱导的67LR依赖性细胞死亡的速率决定过程。我们发现磷酸二酯酶5 （PDE5）是cGMP的负调节因子，在多种癌症和67lr介导的细胞死亡中异常表达。伐地那非是一种用于治疗勃起功能障碍的PDE5抑制剂，在不影响正常细胞的情况下，显著增强egcg激活的67lr依赖性细胞凋亡，并延长小鼠异种移植模型的存活时间。这些结果表明，PDE5抑制剂可以通过提高cGMP水平来诱导67lr介导的癌症特异性细胞死亡。
The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a. vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKC delta/acid sphingomyelinase (PKC delta/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.